The cochlear implant is considered to be the standard treatment for bilateral profound sensorineural hearing loss. However, there remains significant variability in the functional results of implantation as assessed by word recognition scores. In addition, recent evidence suggests a significant cellular immunologic response may occur in the presence of an implant in most individuals. This response may interfere with the postoperative results of implantation and also may preclude future regenerative therapy. In an effort to elucidate the cause of pathologic changes induced in the inner ear as a consequence of cochlear implantation during life, this grant submission proposes three specific aims. Aim 1 will evaluate the preservation of cells of the organ Corti and their innervating dendritic processes following cochlear implantation in the human and build on preliminary data generated during the previous grant period. A battery of immunostains was identified which will be used in human adult specimens to determine the preservation of hair cells, supporting cells (some of which are putative progenitor cells) and neurons and will be applied to temporal bone specimens from 21 patients who in life had undergone cochlear implantation. Aim 2 will further evaluate the immune response to the presence of a cochlear implant in the human using immunohistochemical and morphometric techniques. Specifically we will test the hypotheses that a) postoperative word recognition scores are negatively correlated with the severity of intracochlear new bone and fibrous tissue (Aim 2A); b) macrophages and microglia- like cells play a role in the cellular immune response (Aim 2B); c) the silicone carrier surrounding the cochlear electrode plays a role in the cellular inflammatory response (Aim 2C); d) finally, the fibrous capsule surrounding the implant is not symmetrically deposited which may imply that other mechanisms (such as electrical stimulation) may also be responsible for the inflammatory response. In Aim 3, continued accrual of temporal bones from patients who in life underwent cochlear implantation is planned. It is hoped that this research will elucidate better methods of manufacture and surgery to limit the immune response to cochlear implantation and also elucidate the feasibility of applying future regenerative biologic techniques to restore hearing in patients who have already undergone cochlear implantation during life.